Dorsolateral Prefrontal Cortex Function Research Articles

Insights from a Career at the Border of Developmental Psychology and Cognitive Neuroscience

Much has changed since I started my PhD research in 1980. Neither the field of developmental cognitive neuroscience nor the term “executive functions” existed then. In some ways this piece is backward-looking, such as discussing how our research introduced the importance of the executive function of inhibitory control for cognitive development and that infants and young children are much smarter than we thought. The way our field has queried infants and young children often prevented us from seeing their competencies. That is still too true in studying children from different backgrounds. In other ways, this piece is forward-looking, such as when discussing evidence that the conceptualization of working memory as an executive function and as the key function of dorsolateral prefrontal cortex has been too narrow. It is not just separation in time that must be bridged (traditionally the province of working memory) but also separations in space, and the latter are just as important for cognitive development and just as dependent on the executive function brain network, including dorsolateral prefrontal cortex. It is also forward-looking in discussing the critical importance of motor, social, and emotional development for cognitive development and executive functions, as well as bidirectional relations among these different facets of development. Study of the different aspects of human development are still far too siloed, as are the different fields of science. Examples are provided of how the fields of neuroscience (including neurochemistry and molecular genetics) and child development inform and complement one another. Implications for educators, parents, and researchers are interwoven throughout.

Impact of high-frequency rTMS combined with pharmacotherapy on the left dorsolateral prefrontal cortex in treating major depressive disorder: A real-world study

BackgroundRepetitive transcranial magnetic stimulation (rTMS) combined with pharmacotherapy is a promising treatment method for depression. However, its treatment mechanism needs further research. MethodsThis study recruited 38 healthy individuals (HC) and 52 patients with severe depression (MDD) and divided patients into two treatment groups: the rTMS combined antidepressant (rTMS+ADP) group and the single antidepressant (ADP) group. We used functional magnetic resonance imaging to calculate the fractional amplitude of low-frequency fluctuations (fALFF) in the left dorsolateral prefrontal cortex (DLPFC) to investigate the functional change after treatment. ResultThe fALFF in the left DLPFC was significantly lower in the MDD group than that in the HC group (p < 0.05). In addition, fALFF values of the left DLPFC negatively correlated with HAMD-24 scores (r = −0.294, p = 0.005). After treatment, both MDD groups showed a significant decrease in HAMD-24 scores, with a response rate of 88.89 % and a remission rate of 62.96 % in the rTMS+ADP group, compared to 64 % response and 56 % remission rates in the ADP group. The fALFF values in patients' left DLPFC significantly reduced in the rTMS+ADP group (p < 0.05), but not in the ADP group. LimitationsOur study only focused on the treatment effect in the left DLPFC, without exploring the other brain regions or networks. ConclusionsThis study emphasizes the significance of the left DLPFC in MDD treatment. However, combined left DLPFC rTMS with ADP causes deviation from the normal resting brain function of the left DLPFC, indicating that future research should explore targeted treatment methods to normalize the left DLPFC.

Synaptic alterations in pyramidal cells following genetic manipulation of neuronal excitability in monkey prefrontal cortex.

In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.

Altered Lateral Prefrontal Cortex Functioning During Emotional Interference Resistance Is Associated With Affect Lability in Adults With Persisting Symptoms of Attention-Deficit/Hyperactivity Disorder From Childhood

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by inattention and/or impulsivity/hyperactivity. ADHD, especially when persisting into adulthood, often includes emotional dysregulation, such as affect lability; however, the neural correlates of emotionality in adults with heterogeneous ADHD symptom persistence remain unclear. MethodsThe present study sought to determine shared and distinct functional neuroanatomical profiles of neural circuitry during emotional interference resistance using the emotional face n-back task in adult participants with persisting (n = 47), desisting (n = 93), or no (n = 42) childhood ADHD symptoms while undergoing functional magnetic resonance imaging. ResultsParticipants without any lifetime ADHD diagnosis performed significantly better (faster and more accurately) than participants with ADHD diagnoses on trials with high cognitive loads (2-back) that included task-irrelevant emotional distractors, tapping into executive functioning and emotion regulatory processes. In participants with persisting ADHD symptoms, more severe emotional symptoms were related to worse task performance. Heightened dorsolateral and ventrolateral prefrontal cortex activation was associated with more accurate and faster performance on 2-back emotional faces trials, respectively. Reduced activation was associated with greater affect lability in adults with persisting ADHD, and dorsolateral prefrontal cortex activation mediated the relationship between affect lability and task accuracy. ConclusionsThese findings suggest that alterations in dorsolateral prefrontal cortex function associated with greater interference in cognitive processes from emotion could represent a marker of risk for problems with emotional dysregulation in individuals with persisting ADHD and thus represent a potential therapeutic target for those with greater emotional symptoms of ADHD.

Neural correlates of drinking reduction during a clinical trial of cognitive behavioral therapy for alcohol use disorder.

Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and goal-directed behavior, plays a role in behavior change during CBT by facilitating the regulation of craving (ROC). Treatment-seeking participants with AUD (N = 22) underwent functional magnetic resonance imaging (fMRI) scanning both before and after a 12-week, single-arm trial of CBT, using an ROC task that was previously shown to engage the DLPFC. We found that both the percentage of heavy drinking days (PHDD) and the overall self-reported alcohol craving measured during the ROC task were significantly reduced from pre- to post-CBT. However, we did not find significant changes over time in either the ability to regulate craving or regulation-related activity in any brain region. We found a significant 3-way interaction between the effects of cue-induced craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on PHDD in the left DLPFC. Follow-up analysis showed that cue-induced craving was associated with cue-induced activity in the left DLPFC among participants who ceased heavy drinking during CBT, both at pre-CBT and post-CBT timepoints. No such associations were present at either timepoint among participants who continued to drink heavily. These results suggest that patients in whom DLPFC functioning is more strongly related to cue-induced craving may preferentially respond to CBT.

Disrupting the Dorsolateral Prefrontal Cortex Attenuates the Difference in Decision-Making for Altruistic Punishment Between the Gain and Loss Contexts.

Altruistic punishment is a primary response to social norms violations; its neural mechanism has also attracted extensive research attention. In the present studies, we applied a low-frequency repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) while participants engaged in a modified Ultimatum Game (Study 1) and third-party punishment game (Study 2) to explore how the bilateral DLPFC disruption affects people's perception of violation of fairness norms and altruistic punishment decision in the gain and loss contexts. Typically, punishers intervene more often against and show more social outrage towards Dictators/Proposers who unfairly distribute losses than those who unfairly share gains. We found that disrupting the function of the left DLPFC in the second-party punishment and the bilateral DLPFC in the third-party punishment with rTMS effectively obliterated this difference, making participants punish unfairly shared gains as often as they usually would punish unfairly shared losses. In the altruistic punishment of maintaining the social fairness norms, the inhibition of the right DLPFC function will affect the deviation of individual information integration ability; the inhibition of the left DLPFC function will affect the assessment of the degree of violation of fairness norms and weaken impulse control, leading to attenuate the moderating effect of gain and loss contexts on altruistic punishment. Our findings emphasize that DLPFC is closely related to altruistic punishment and provide causal neuroscientific evidence.

Effects of transcranial static magnetic field stimulation over the left dorsolateral prefrontal cortex on random number generation

ObjectiveFocal application of transcranial static magnetic field stimulation (tSMS) is a neuromodulation technique, with predominantly inhibitory effects when applied to the motor, somatosensory or visual cortex. Whether this approach can also transiently interact with dorsolateral prefrontal cortex (DLPFC) function remains unclear. The suppression of habitual or competitive responses is one of the core executive functions linked to DLPFC function. This study aimed to assess the impact of tSMS on the prefrontal contributions to inhibitory control and response selection by means of a RNG task. MethodsWe applied 20 min of tSMS over the left DLPFC of healthy subjects, using a real/sham cross-over design, during performance of a RNG task. We used an index of randomness calculated with the measures of entropy and correlation to assess the impact of stimulation on DLPFC function. ResultsThe randomness index of the sequences generated during the tSMS intervention was significantly higher compared to those produced in the sham condition. ConclusionsOur results indicate that application of tSMS transiently modulates specific functional brain networks in DLPFC, which indicate a potential use of tSMS for treatment of neuropsychiatric disorders. SignificanceThis study provides evidence for the capacity of tSMS for modulating DLPFC function.

Plasticity changes in dorsolateral prefrontal cortex associated with procedural sequence learning are hemisphere-specific

Corticocortical neuroplastic changes from higher-order cortices to primary motor cortex (M1) have been described for procedural sequence learning. The dorsolateral prefrontal cortex (DLPFC) plays critical roles in cognition, including in motor learning and memory. However, neuroplastic changes in the DLPFC and their influence on M1 and on motor learning are not well understood. The present study examined bilateral DLPFC–M1 changes in plasticity induced by procedural motor sequence learning in a serial reaction time task. DLPFC plasticity induced by procedural sequence learning was examined by comparing before vs. after training assessments of ipsilateral/contralateral DLPFC–M1 interactions between sequence order and random order trials performed using either the left or right hand. Intra-hemispheric (inter-stimulus interval [ISI] = 10 ms) and inter-hemispheric (ISI = 10 or 50 ms) DLPFC–M1 interactions and single-pulse motor-evoked potentials (MEPs) were measured with transcranial magnetic stimulation (TMS). The reaction times of participants measured during motor training were faster for sequence learning than for random learning with either hand. Paired-pulse TMS induced DLPFC–M1 interactions that were disinhibited after motor sequence learning, especially for left DLPFC–left M1 interactions with right hand task performance and for left DLPFC–right M1 interactions with left hand task performance. These findings indicate that motor sequence learning induces neuroplastic changes to enhance DLPFC–M1 interactions. This manifestation of plasticity showed hemispheric specificity, favoring the left DLPFC. DLPFC plasticity may be a useful index of DLPFC function and may be a treatment target for enhancing DLPFC function and motor learning.

Memory-Based Prediction Deficits and Dorsolateral Prefrontal Dysfunction in Schizophrenia

BackgroundTheories suggest that people with schizophrenia (SZ) have problems generating predictions based on past experiences. The dorsolateral prefrontal cortex (DLPFC) and hippocampus participate in memory-based prediction. We used functional magnetic resonance imaging to investigate DLPFC and hippocampal function in healthy control (HC) subjects and people with SZ during memory-based prediction. MethodsPrior to scanning, HC subjects (n = 54) and people with SZ (n = 31) learned 5-object sequences presented in fixed or random orders on each repetition. During scanning, participants made semantic decisions (e.g., “Can this object fit in a shoebox?”) on a continuous stream of objects from fixed and random sequences. Sequence prediction was demonstrated by faster semantic decisions for objects in fixed versus random sequences because memory could be used to anticipate and more efficiently process semantic information about upcoming objects in fixed sequences. Representational similarity analyses were used to determine how each sequence type was represented in the posterior hippocampus and DLPFC. ResultsSequence predictions were reduced in individuals with SZ relative to HC subjects. Representational similarity analyses revealed stronger memory-based predictions in the DLPFC of HC subjects than people with SZ, and DLPFC representations correlated with more successful predictions in HC subjects only. For the posterior hippocampus, voxel pattern similarity was increased for fixed versus random sequences in HC subjects only, but no significant between-group differences or correlations with prediction success were observed. ConclusionsIndividuals with SZ are capable of learning temporal sequences; however, they are impaired using memory to predict upcoming events as efficiently as HC subjects. This deficit appears related to disrupted neural representation of sequence information in the DLPFC.

The impact of transparency on hemispheric lateralization of idiom comprehension: An rTMS study

Previous neuropsychological data have equivocal suggestions concerning hemispheric involvement during idiom comprehension. The possible contribution of idioms transparency to the lateralization of figurative language comprehension has not been investigated using an interference technique. To analyse the cortical lateralization of idiom transparency processing, we employed inhibitory repetitive transcranial magnetic stimulation (rTMS) to the left and right dorsolateral prefrontal cortex (DLPFC) during the processing of opaque idioms, transparent idioms, and non-idiomatic literal phrases. Based on the Coarse Semantic Coding theory, we predicted a greater right hemisphere involvement when processing opaque than transparent idioms. Eighteen young healthy participants underwent rTMS pulses at 1 Hz frequency, 110% of motor threshold intensity for 15 min (900 pulses) in two sessions at one-week intervals. In a semantic decision task, participants judged the relatedness of an idiom and a target word. The target word was figuratively or literally related to the idiom, or unrelated. The study also included non-idiomatic sentences. We found that left DLPFC functions are more critical for comprehension of opaque rather than transparent idioms when referring to the figurative associations of the idioms. Opaque idioms, in the context of their figurative meaning, rely more heavily on left hemisphere resources. This finding suggests that opaque idioms are seemingly processed as one unit. Taken together, we believe that the transparency of idiomatic expressions may play an important role in modulating hemispheric functions involved in figurative language processing.

Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia.

Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having "an orchestra without a conductor." Kraepelin further speculated that this "conductor" was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.

Evaluation of hemodynamic changes using near-infrared spectroscopy in patients with tic-related obsessive-compulsive disorder.

A tic-related specifier is included in the DSM-5 diagnostic criteria to identify a clinically specific obsessive-compulsive disorder (OCD) subtype. The current study sought to evaluate hemodynamic changes during executive function tasks among OCD patients with and without a lifetime history of tic disorder (TD) and healthy controls, and to investigate the relation between brain activation and clinical variables in each group using structured equation modeling. Twenty-nine OCD patients diagnosed according to the DSM-IV-TR and 15 healthy controls were recruited. Patients were divided into two groups according to the presence or absence of a lifetime history of TD (TD+, n = 11; TD-, n = 18). Prefrontal hemodynamic changes were measured using multi-channel near-infrared spectroscopy during the Verbal Fluency Task, Trail-Making Task, and Tower of London (ToL) Task. There were significant brain activation differences in the frontopolar cortex between OCD patients with and without TD during Verbal Fluency Task and ToL performance. Brain activation in the dorsolateral prefrontal cortex (DLPFC) during the ToL Task in OCD patients with TD exerted a direct causal effect on the severity of compulsions. In addition, we detected a direct causal effect of the severity of obsessions in OCD patients without TD on brain activation in the DLPFC during the ToL Task. Brain activation in the frontopolar cortex exhibits different hemodynamics depending on the task, and DLPFC function may play a different role in the neural basis of developing OCD symptoms between OCD patients with and without TD.

Independent Contributions of Dorsolateral Prefrontal Structure and Function to Working Memory in Healthy Older Adults.

Age-related differences in dorsolateral prefrontal cortex (DLPFC) structure and function have each been linked to working memory. However, few studies have integrated multimodal imaging to simultaneously investigate relationships among structure, function, and cognition. We aimed to clarify how specifically DLPFC structure and function contribute to working memory in healthy older adults. In total, 138 participants aged 65-88 underwent 3T neuroimaging and were divided into higher and lower groups based on a median split of in-scanner n-back task performance. Three a priori spherical DLPFC regions of interest (ROIs) were used to quantify blood-oxygen-level-dependent (BOLD) signal and FreeSurfer-derived surface area, cortical thickness, and white matter volume. Binary logistic regressions adjusting for age, sex, education, and scanner type revealed that greater left and right DLPFC BOLD signal predicted the probability of higher performing group membership (P values<.05). Binary logistic regressions also adjusting for total intracranial volume revealed left DLPFC surface area that significantly predicted the probability of being in the higher performing group (P = 0.017). The left DLPFC BOLD signal and surface area were not significantly associated and did not significantly interact to predict group membership (P values>.05). Importantly, this suggests BOLD signal and surface area may independently contribute to working memory performance in healthy older adults.

Causal role of lateral prefrontal cortex in mental effort and fatigue.

Dorsolateral prefrontal cortex (DLPFC) is well‐known for its role in exerting mental work, however the contribution of DLPFC for deciding whether or not to engage in effort remains unknown. Here, we assessed the causal role of DLPFC in effort‐based decision making. We disrupted functioning of DLPFC with noninvasive brain stimulation before participants repeatedly decided whether to exert mental effort in a working memory task. We found the same DLPFC subregion involved in mental effort exertion to influence also effort‐based decisions: First, it enhanced effort discounting, suggesting that DLPFC may signal the capacity to successfully deal with effort demands. Second, a novel computational model integrating the costs of enduring effort into the effort‐based decision process revealed that DLPFC disruption reduced fatigue after accumulated effort exertion, linking DLPFC activation with fatigue. Together, our findings indicate that in effort‐based decisions DLPFC represents the capacity to exert mental effort and the updating of this information with enduring time‐on‐task, informing theoretical accounts on the role of DLPFC in the motivation to exert mental effort and the fatigue arising from it.

Promising Neuroimaging Biomarkers in Depression.

The neuroimaging has been applied in the study of pathophysiology in major depressive disorder (MDD). In this review article, several kinds of methodologies of neuroimaging would be discussed to summarize the promising biomarkers in MDD. For the magnetic resonance imaging (MRI) and magnetoencephalography field, the literature review showed the potentially promising roles of frontal lobes, such as anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). In addition, the limbic regions, such as hippocampus and amygdala, might be the potentially promising biomarkers for MDD. The structures and functions of ACC, DLPFC, OFC, amygdala and hippocampus might be confirmed as the biomarkers for the prediction of antidepressant treatment responses and for the pathophysiology of MDD. The functions of cognitive control and emotion regulation of these regions might be crucial for the establishment of biomarkers. The near-infrared spectroscopy studies demonstrated that blood flow in the frontal lobe, such as the DLPFC and OFC, might be the biomarkers for the field of near-infrared spectroscopy. The electroencephalography also supported the promising role of frontal regions, such as the ACC, DLPFC and OFC in the biomarker exploration, especially for the sleep electroencephalogram to detect biomarkers in MDD. The positron emission tomography (PET) and single-photon emission computed tomography (SPECT) in MDD demonstrated the promising biomarkers for the frontal and limbic regions, such as ACC, DLPFC and amygdala. However, additional findings in brainstem and midbrain were also found in PET and SPECT. The promising neuroimaging biomarkers of MDD seemed focused in the fronto-limbic regions.

A preliminary study of association between adolescent estradiol level and dorsolateral prefrontal cortex activity during emotion regulation

Non-human primate models have been useful in clarifying estradiol’s role in cognitive processing. These animal studies indicate estradiol impacts cognitive processes supported by regions within dorsolateral prefrontal cortex (DLPFC). Although human functional neuroimaging studies have begun to find similar relationships between estradiol in women for some forms of ‘cold’ cognitive control, to date no studies have examined the relationship between estradiol and DLPFC function in the context of active attempts to regulate one’s emotions. Here, we asked whether peripheral 17-beta estradiol levels in adolescent girls in different pubertal developmental stages (age = 14.9 years ± 1.74) were related to engagement of DLPFC regions during the use of a cognitive strategy for regulating emotion known as reappraisal using functional Magnetic Resonance Imaging. Findings indicated that higher estradiol levels predicted greater DLPFC activity during the down-regulation of negative emotion using reappraisal. This is the first report of an association between estradiol level and DLPFC activity during cognitive reappraisal of negative emotion. The study suggests a possibility that estradiol might positively contribute to regulatory function of a cortical system important for emotional experiences.

The intricate relationship between stress and sex - findings from the men stress 40+ study

Non-human primate models have been useful in clarifying estradiol’s role in cognitive processing. These animal studies indicate estradiol impacts cognitive processes supported by regions within dorsolateral prefrontal cortex (DLPFC). Although human functional neuroimaging studies have begun to find similar relationships between estradiol in women for some forms of ‘cold’ cognitive control, to date no studies have examined the relationship between estradiol and DLPFC function in the context of active attempts to regulate one’s emotions. Here, we asked whether peripheral 17-beta estradiol levels in adolescent girls in different pubertal developmental stages (age = 14.9 years ± 1.74) were related to engagement of DLPFC regions during the use of a cognitive strategy for regulating emotion known as reappraisal using functional Magnetic Resonance Imaging. Findings indicated that higher estradiol levels predicted greater DLPFC activity during the down-regulation of negative emotion using reappraisal. This is the first report of an association between estradiol level and DLPFC activity during cognitive reappraisal of negative emotion. The study suggests a possibility that estradiol might positively contribute to regulatory function of a cortical system important for emotional experiences.

Low-frequency rTMS stimulation over superior parietal cortex medially improves time reproduction and increases the right dorsolateral prefrontal cortex predominance

Aim of the study: Previous studies have shown that several cortical regions are involved in temporal tasks in multiple timescales. However, the hemispheric predominance of the dorsolateral prefrontal cortex (DLPFC) during time reproduction after repetitive low-frequency transcranial magnetic stimulation (rTMS) is relatively unexplored. Here, we study the effects of 1 Hz rTMS and sham stimulation applied medially over the superior parietal cortex (SPC) on the DLPFC alpha and beta band asymmetry and on time reproduction.Materials and methods: For this purpose, we have combined rTMS with electroencephalography in 20 healthy subjects who performed the time reproduction task in two conditions (sham and 1 Hz).Results: The worst performance was observed in sham and 1Hz conditions for longer time intervals (p < .05), with the 1Hz condition subjects sub-reproducing the time interval, closer to the target interval (p < .05). The right DLPFC hemispheric predominance was found in both conditions, but after low-frequency rTMS, the right hemisphere predominance increased in the 1Hz condition (p < .05).Conclusions: Results of this study suggest that rTMS applied over the SPC influences time interval interpretation and the DLPFC functions. Future studies would explore the effects of the rTMS application to other cortical areas, and study how it influences time interval interpretation.

Distinguishing the roles of dorsolateral and anterior PFC in visual metacognition

Visual metacognition depends on regions within the prefrontal cortex (PFC). Two areas in particular have been implicated repeatedly: the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we used online transcranial magnetic stimulation (TMS) to interfere causally with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision making and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability, but only for the second half of the experimental blocks. These results support a functional architecture in which DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgment by potentially incorporating additional, nonperceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation.SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its subregions, the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC), have been specifically implicated in confidence generation. However, it is unclear whether these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation, we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, whereas targeting aPFC affected metacognitive scores specifically. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation.

Distinguishing the Roles of Dorsolateral and Anterior PFC in Visual Metacognition.

Visual metacognition depends on regions within the prefrontal cortex (PFC). Two areas in particular have been implicated repeatedly: the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we used online transcranial magnetic stimulation (TMS) to interfere causally with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision making and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability, but only for the second half of the experimental blocks. These results support a functional architecture in which DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgment by potentially incorporating additional, nonperceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation.SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its subregions, the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC), have been specifically implicated in confidence generation. However, it is unclear whether these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation, we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, whereas targeting aPFC affected metacognitive scores specifically. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation.